Reducing the particle size of a water-insoluble drug often increases the drug's bioavailability. Milling techniques, such as jet milling, ball milling and wet grinding, can be used to reduce the particle size of some drugs, but these techniques cannot be used in some situations due to the possibility of contaminating the drug with grinding media residue or the possibility of degrading the drug due to high shear forces.
Emulsion-based precipitation techniques have been proposed as an alternative means to reduce the particle size of water-insoluble drugs. In these techniques, the water-insoluble drug is dissolved in an organic solvent to form a solution, which is then emulsified in water to become the discontinuous organic (“oil”) phase of an oil-in-water (“o/w”) emulsion. Small particles can be obtained by removing the organic solvent from the organic phase of the emulsion via evaporation, solvent diffusion and/or by supercritical fluid extraction.
Two factors that are known to significantly affect the particle size and distribution of particles produced using emulsion-based techniques are: (1) the size and uniformity of the oil phase emulsion droplets; and (2) the stability of the emulsion. The particle size and size distribution of the particles produced is directly proportional to the size of the emulsion droplets. Furthermore, it is very difficult to obtain small particles in a narrow size distribution when the emulsion is not sufficiently stable during processing. Some water-insoluble drugs are difficult to incorporate into emulsions, and the presence of such water-insoluble drugs in the oil phase of the emulsion tends to render the emulsion unstable, which leads to emulsion droplet coalescence and/or phase separation and thus poor particle size uniformity upon precipitation.